Heart failure remains an important cause of morbidity and mortality in cardiovascular disease. The diminished inotropic response of the failing myocardium appears to be mediated in part by defects in the beta- adrenergic signal transduction complex. Recent studies suggest perturbations in G-protein subunits may contribute to decreased inotropism. The functional denervation of the human transplanted heart may contribute to altered G-protein composition. The long term objective is an improved understanding of G-proteins and how they modulate beta- adrenergic signal transduction in the failing and transplanted human heart. The hypothesis is that relative alterations in G-protein subunits affect beta-adrenergic-G-protein-adenylyl cyclase signal transduction, are associated and possibly contribute to the development and/or sustaining of heart failure, and this can be detected by determination of changes in relative levels of mRNA encoding G-protein subunits. The aims of this proposal are: 1) define the G-protein composition in the human heart, 2) define the alterations in G-protein subunit composition and extent of these changes, 3) determine the relationship between the severity of heart failure and extent of G-protein alteration with the progression of heart failure, 4) determine if hemodynamic unloading of the ventricle reverses G-protein alterations, and 5) define the G-protein alteration in the human transplanted heart. G-protein subunits are quantitated in normal, transplanted, and failing hearts. Using molecular cloning techniques, G-protein subunit mRNA is identified and relative quantitation achieved with a competitive, quantitative polymerase chain reaction. The altered gene expression is correlated with G-protein subunit levels quantitated with immunoblotting. An elucidation of the complex regulation of G-protein subunits and beta-adrenergic membrane signaling in man may lead to new therapeutic or pharmacologic modalities for the treatment of heart failure.